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INTRODUCTIONDementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here, we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimers disease (AD)-free participants. METHODSAssociations between dementia risk measures (family history, genetic risk score (GRS), and dementia risk scores (combining lifestyle, demographic and genetic factors) and whole-blood DNA methylation were assessed in discovery and replication samples (n=[~]400 - [~]5,000) from Generation Scotland. RESULTSAD genetic risk and two risk scores were associated with differential methylation. The GRS predominantly associated with methylation differences in cis but also identified a genomic region implicated in Parkinsons disease. Loci associated with the risk scores were enriched for those previously associated with body mass index and alcohol consumption. DISCUSSIONDementia risk measures show widespread association with blood-based methylation, which indicates differences in the processes affected by genetic and demographic/lifestyle risk factors.

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